This invention relates to a process for preparing 2-benzoyl-3,3-dimethyl-7-oxo-.alpha.-[4-(benzyloxy)phenyl]-4-thia-2,6-diaz abicyclo[3.2.0]heptane-6-acetic acid, benzyl ester which is represented by the following structural formula ##STR2## wherein the 3-centers of asymmetry have the indicated configuration. This invention is concerned with a process for epimerizing the asymmetric center attached to the N of the azetidinone ring of the above compound.
The bicyclic compound represented by the above formula is referred to herein for convenience as a thiazolidine-azetidinone. The compound in the D-configuration is useful as an intermediate in the process for the preparation of the antibiotic substance nocardicin which is described in co-pending application Ser. No. 739,161 filed Nov. 5, 1976. As described therein, the thiazolidine-azetidinone having the D-configuration is a preferred isomer of the intermediate in the preparation of nocardicin. In the described process, the preparation of the thiazolidine-azetidinone is carried out as illustrated in the reaction schemes below. L-cysteine is heated with acetone and the product, 2,2-dimethylthiazolidine-4-carboxylic acid (1), is acylated with benzoyl chloride in the presence of a hydrogen halide acceptor to provide the 2,2-dimethyl-3-benzoylthiazolidine-4-carboxylic acid (2). The 3-benzoyl thiazolidine-4-carboxylic acid is then converted to the amide (3) formed with the benzyl ester of 4-benzyloxyphenylglycine. The formation of the amide is conveniently carried out by first converting the thiazolidine carboxylic acid to the active ester formed with 1-hydroxybenzotriazole. The formation of the active ester is carried out by condensing the acid with the hydroxybenzotriazole in the presence of a condensing agent such as dicyclohexylcarbodiimide. The active ester of the thiazolidine carboxylic acid is then used to acylate the .alpha.-amino group of the phenylglycine to form the amide (3). ##STR3##
The thiazolidine amide (3) is converted to the cyclic thiazolidine-azetidinone as shown in the following reaction scheme. ##STR4##
As shown above, the thiazolidine amide (3) is first converted to the 5.alpha.-benzoate derivative (4) by reacting (3) with benzoyl peroxide. The reaction is carried out by heating the amide in an inert solvent with benzoyl peroxide. Suitable solvents include the hydrocarbon solvents such as benzene and toluene, or the chlorinated hydrocarbon solvents such as methylene chloride and chloroform. An excess of benzoyl peroxide is employed and preferably between about a 2 and 4 molar excess.
The 5.alpha.-benzoate (4), which can be purified and separated from unreacted starting material by chromatography over silica gel, is then reacted with hydrogen chloride in an inert solvent at a temperature between about -20.degree. and about 5.degree. C. to form the corresponding 5.alpha.-chloro thiazolidine amide represented by the above Formula (3). The reaction is conveniently carried out in a chlorinated hydrocarbon solvent such as methylene chloride or chloroform, and the progress of the reaction can be followed by thin layer chromatography.
The 5.alpha.-chloro compound (5) on treatment under anhydrous conditions with a strong base such as sodium hydride or 1,5-diazabicyclo[5.4.0]undec-5-ene (DBU) undergoes cyclization to form the bicyclic thiazolidine-azetidinone.
The cyclization is carried out at a temperature between about 0.degree. and 30.degree. C. in an inert solvent. Suitable solvents include those previously mentioned in connection with the foregoing reactions, for example, the halogenated hydrocarbon solvents such as chloroform, DMF and methylene chloride, and trichloroethane. The product of the cyclization is best purified by chromatography over silica gel. Gradient elution employing a gradient of benzene to benzeneethyl acetate (7:3, v:v) is a suitable chromatographic system.
The base catalyzed cyclization of the 5.alpha.-chlorothiazolidine carboxamide results in epimerization of the asymmetric center in the phenylglycine portion of the amide. Accordingly, when D-phenylglycine is employed as starting material in the preparation of the bicyclic thiazolidine-azetidinone, the base catalyzed cyclization results in epimerization leading to a mixture of the D- and L-thiazolidine-azetidinones. Although the D- and L-isomers can be separated from each other by fractional crystallization, the process provided by this invention allows one to convert the L-isomer to the preferred D-isomer.